Development of a predictive model for nephrotoxicity during tacrolimus treatment using machine learning methods.

AIM: When administering tacrolimus, therapeutic drug monitoring is recommended because nephrotoxicity, an adverse event, occurs at supra-therapeutic whole-blood concentrations of tacrolimus. However, some patients exhibit nephrotoxicity even at the recommended concentrations, therefore establishing a therapeutic range of tacrolimus concentration for the individual patient is necessary to avoid nephrotoxicity. This study aimed to develop a model for individualized prediction of nephrotoxicity in patients administered tacrolimus. METHODS: We collected data, such as laboratory test data at tacrolimus initiation, concomitant drugs and tacrolimus whole-blood concentration, from medical records of patients who received oral tacrolimus. Nephrotoxicity was defined as an increase in serum creatinine levels within 60 days of tacrolimus initiation. We built 13 prediction models based on different machine learning algorithms: logistic regression, support vector machine, gradient-boosting trees, random forest and neural networks. The best performing model was compared with the conventional model, which classifies patients according to the tacrolimus concentration alone. RESULTS: Data from 163 and 41 patients were used to construct models and evaluate the best performing one, respectively. Most of the patients were diagnosed with inflammatory or autoimmune diseases. The best performing model was built using a support vector machine; it showed a high F2 score of 0.750 and outperformed the conventional model (0.500). CONCLUSIONS: A machine learning model to predict nephrotoxicity in patients during tacrolimus treatment was developed using tacrolimus whole-blood concentration and other patient data. This model could potentially assist in identifying high-risk patients who require individualized target therapeutic concentrations of tacrolimus prior to treatment initiation to prevent nephrotoxicity.

Paliperidone-Induced Acute Hyperglycemia Is Caused by Adrenaline Secretion via the Activation of Hypothalamic AMP-Activated Protein Kinase.

Although paliperidone-related hyperglycemia has been extensively examined, the underlying mechanisms have not yet been elucidated. We investigated the effects of a single intravenous injection of paliperidone (0.2, 0.4, or 0.6 mg/kg) on serum concentrations of glucose and other endogenous metabolites in rats. We also examined the effects of a single intravenous injection of paliperidone (0.4 mg/kg) on AMP-activated protein kinase (AMPK) activity in the hypothalamus and liver. To clarify the relationship between AMPK activity and adrenaline secretion, the effects of berberine, which inhibits hypothalamic AMPK, on paliperidone-induced hyperglycemia were assessed. Significant increases were observed in serum glucose, adrenaline, and insulin concentrations following intravenous injections of paliperidone at doses of 0.4 and 0.6 mg/kg. A propranolol pretreatment attenuated paliperidone-induced increases in serum concentrations of glucose, but not adrenaline. Significant increases were also noted in phosphorylated AMPK concentrations in the hypothalamus following the administration of paliperidone at a dose of 0.4 mg/kg. A berberine pretreatment attenuated paliperidone-induced increases in blood concentrations of glucose, adrenaline, and insulin and phosphorylated AMPK concentrations in the hypothalamus. Collectively, the present results demonstrated that an acute treatment with paliperidone induced hyperglycemia, which was associated with the effects of hypothalamic AMPK activation on the secretion of adrenaline.

Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases.

PURPOSE: The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID). METHODS: We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID. RESULTS: The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival. CONCLUSIONS: RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.

Intravenous Infusion of Fentanyl Has No Effect on Blood Concentration of Tacrolimus in Patients Receiving Hematopoietic Stem-Cell Transplantation.

BACKGROUND: Both tacrolimus (TAC) and fentanyl are frequently used in patients receiving allogeneic hematopoietic stem-cell transplantation. A recently published report demonstrated that fentanyl can reduce the total body clearance of TAC; however, most patients in this study were administered concomitantly with azole antifungal agents, which are known to be strong inhibitors of CYP3A. Hence, the exact effect of fentanyl on TAC pharmacokinetics was unclear. In the current study, the authors retrospectively investigated the pharmacokinetic interaction between TAC and fentanyl in patients who were not concomitantly administered drugs that affect TAC metabolism. METHODS: Patients with continuous infusion of TAC and fentanyl after hematopoietic stem-cell transplantation at the Tokyo Medical and Dental University between January 2014 and December 2018 were enrolled. The total body clearance of TAC was compared before and after the initiation or discontinuation of fentanyl. RESULTS: Thirty patients (24 men and 6 women; median age, 11 years) were screened for their eligibility. Twenty-eight patients were enrolled for evaluating the effects of the fentanyl initiation on TAC pharmacokinetics; 2 patients were excluded because of the absence of data related to the TAC blood concentrations or the concomitant use of azole antifungals. Twenty patients were enrolled for investigating the effects of fentanyl discontinuation on TAC pharmacokinetics, whereas 10 patients were excluded because of the absence of data related to the blood concentration of TAC or the additional administration of azole antifungals. Furthermore, the total body clearance of TAC was not significantly affected by the initiation or discontinuation of fentanyl, although there were large interindividual variations. In addition, the results remained the same even when the analysis was performed independently for adults and children. CONCLUSIONS: Intravenous infusion of fentanyl does not affect the pharmacokinetics of TAC.

Clozapine-Induced Acute Hyperglycemia Is Accompanied with Elevated Serum Concentrations of Adrenaline and Glucagon in Rats.

Clozapine, an atypical antipsychotic agent, has been reported to cause acute hyperglycemia. However, the mechanism of clozapine-induced rapidly developing hyperglycemia is not well elucidated. To clarify the mechanism underlying clozapine-induced acute hyperglycemia, we investigated the effects of single intravenous administration of clozapine on the serum concentrations of glucose and several endogenous substances in rats. Male Wistar rats received an intravenous injection of saline (control) or clozapine 2.5, 5, 10 mg/kg. Blood samples were obtained periodically after clozapine administration to determine the serum concentrations of glucose, adrenaline, glucagon, insulin, corticosterone, and clozapine. The serum concentrations of glucose, adrenaline, and glucagon increased dose-dependently after the administration of clozapine at 2.5-10 mg/kg, and reached maxima at 5 mg/kg of clozapine. The serum concentration of corticosterone increased after the administration of clozapine, but no significant variation was observed with the dosage of clozapine. The concentration of serum insulin increased in a dose-dependent manner after clozapine administration. In conclusion, a single administration of clozapine increased the serum concentration of glucose in rats, and adrenaline and/or glucagon would be associated with clozapine-induced acute hyperglycemia.

Association of schizophrenia onset age and white matter integrity with treatment effect of D-cycloserine: a randomized placebo-controlled double-blind crossover study.

BACKGROUND: It has been reported that drugs which promote the N-Methyl-D-aspartate-type glutamate receptor function by stimulating the glycine modulatory site in the receptor improve negative symptoms and cognitive dysfunction in schizophrenia patients being treated with antipsychotic drugs. METHODS: We performed a placebo-controlled double-blind crossover study involving 41 schizophrenia patients in which D-cycloserine 50 mg/day was added-on, and the influence of the onset age and association with white matter integrity on MR diffusion tensor imaging were investigated for the first time. The patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Brief Assessment of Cognition in Schizophrenia (BACS), and other scales. RESULTS: D-cycloserine did not improve positive or negative symptoms or cognitive dysfunction in schizophrenia. The investigation in consideration of the onset age suggests that D-cycloserine may aggravate negative symptoms of early-onset schizophrenia. The better treatment effect of D-cycloserine on BACS was observed when the white matter integrity of the sagittal stratum/ cingulum/fornix stria terminalis/genu of corpus callosum/external capsule was higher, and the better treatment effect on PANSS general psychopathology (PANSS-G) was observed when the white matter integrity of the splenium of corpus callosum was higher. In contrast, the better treatment effect of D-cycloserine on PANSS-G and SANS-IV were observed when the white matter integrity of the posterior thalamic radiation (left) was lower. CONCLUSION: It was suggested that response to D-cycloserine is influenced by the onset age and white matter integrity. TRIAL REGISTRATION: UMIN Clinical Trials Registry (number UMIN000000468 ). Registered 18 August 2006.

Effects of Miconazole Oral Gel on Blood Concentrations of Tacrolimus and Cyclosporine: A Retrospective Observational Study.

BACKGROUND: Although azole antifungal agents have been shown to affect the pharmacokinetics of calcineurin inhibitors such as tacrolimus (TAC) and cyclosporine (CyA) by inhibiting drug metabolism, there are few clinical reports on drug interactions between miconazole (MCZ) oral gel and calcineurin inhibitors. In this study, the effects of MCZ oral gel on the blood concentrations of TAC and CyA were investigated. METHODS: In this retrospective study, 18 patients concomitantly administered MCZ oral gel and TAC (9 for dermatomyositis, 3 for myasthenia gravis, 2 for systemic lupus erythematosus, 2 for rheumatoid arthritis, 1 for polymyositis, 1 for prevention of graft-versus-host disease after bone marrow transplantation), and 15 patients concomitantly administered MCZ oral gel and CyA (11 for interstitial pneumonia, 2 for pemphigus, 1 for eosinophilic granulomatosis with polyangiitis, 1 for systemic lupus erythematosus) were evaluated. The dose-adjusted blood concentrations of TAC or CyA were compared before and after the initiation of MCZ oral gel. RESULTS: The trough blood concentration/dose (C/D) ratios of TAC and CyA increased significantly with the administration of MCZ oral gel. The median C/D ratios of TAC and CyA increased by 108% (range: -44% to 216%) and 44% (range: -34% to 195%), respectively. CONCLUSIONS: These results suggest that MCZ oral gel affects the pharmacokinetics of TAC and CyA. Detailed monitoring of the blood concentrations of these drugs, followed by dose adjustments, is needed for each patient because of the difficulties associated with accurately predicting the degree of the effects of MCZ oral gel.

Haploidentical Bone Marrow Transplantation With Clofarabine and Busulfan Conditioning for a Child With Multiple Recurrent Acute Lymphoblastic Leukemia.

Outcome of children with acute lymphoblastic leukemia (ALL) has improved over the years, but not for those with multiple recurrences because of high therapy resistance and heavily pretreated history that potentially cause physical damages. We describe the case of an 11-year-old boy with a third relapse of ALL and a history of 2 allogeneic bone marrow transplantations. He was successfully treated with clofarabine combination chemotherapy and achieved a fourth remission at 16 months following haploidentical bone marrow transplantation with conditioning regimen of clofarabine and busulfan. Clofarabine/busulfan conditioning might be a preferable option for children with multiple recurrent ALL, and warrants further investigation.

Mechanism Underlying Induction of Hyperglycemia in Rats by Single Administration of Olanzapine.

Acute administration of olanzapine rapidly elevates blood glucose levels. However, the mechanism underlying the rapid development of hyperglycemia with the administration of olanzapine remains unclear. The aim of the present study was to clarify the mechanism underlying olanzapine-induced acute hyperglycemia. Male Wistar rats received an intravenous infusion of saline (control) or olanzapine 2.5, 5, or 10 mg/kg. Blood samples were obtained periodically after olanzapine infusion to determine serum concentrations of glucose, olanzapine, and several endogenous substances. In a separate experiment, rats received an intravenous injection of propranolol (2 mg/kg) 30 min before infusion of olanzapine (10 mg/kg). The intravenous infusion of olanzapine induced dose-dependent increases in the serum concentrations of glucose, epinephrine, and insulin. Pretreatment with propranolol suppressed olanzapine-induced elevations in the serum concentration of glucose, but did not affect the serum concentration of olanzapine or olanzapine-induced increase in the serum concentration of epinephrine. Although the serum concentration of corticosterone increased after administration of olanzapine, no significant differences were observed among the olanzapine dose groups. Furthermore, administration of olanzapine did not affect the serum concentration of glucagon or histamine. We developed a pharmacokinetic-pharmacodynamic model assuming that the olanzapine-induced secretion of epinephrine leads to elevated serum glucose concentrations. This model appeared to satisfactorily characterize olanzapine-induced hyperglycemia. In conclusion, a single intravenous dose of olanzapine dose-dependently increased the serum concentration of glucose in rats, and epinephrine plays a role in olanzapine-induced acute hyperglycemia.

Pharmacokinetic-pharmacodynamic analysis of sunitinib-induced thrombocytopenia in Japanese patients with renal cell carcinoma.

The aim of the present study was to clarify the therapeutic range and adequate dose of sunitinib in Japanese renal cell carcinoma patients by means of a pharmacokinetic-pharmacodynamic analysis of sunitinib-induced thrombocytopenia. Six patients with renal cell carcinoma were enrolled in this study. After starting the sunitinib treatment, between three and seven blood samples were obtained from each patient just before the administration of sunitinib. Serum concentrations of sunitinib and its active metabolite N-desethyl-sunitinib were fit to the 1-compartment model with first-order absorption. Changes in platelet counts were fit to the pharmacokinetic-pharmacodynamic model, in which the proliferation of platelet progenitor cells was assumed to be linearly inhibited by sunitinib and its metabolite. All patients using 50 mg as an initial dose of sunitinib developed grade 2 or 3 thrombocytopenia. The pharmacokinetic-pharmacodynamic model created successfully described the time course of sunitinib-induced thrombocytopenia and could predict changes in platelet counts after alterations to the dosage of sunitinib administered. The simulation results indicated that the total trough level of sunitinib to avoid severe thrombocytopenia should be <100 ng/mL, and also that the initial daily dose of sunitinib could be reduced to 37.5 mg or 25 mg in most Japanese patients. In addition to the pharmacokinetic-guided dosage adjustment, the careful monitoring of platelet counts is required for the safe use of sunitinib.

Effects of moxifloxacin on serum glucose concentrations in rats.

Moxifloxacin, a fluoroquinolone antimicrobial agent, has been reported to cause serum glucose abnormalities such as hyper- and hypoglycemia. The purpose of the present study was to investigate the effect of moxifloxacin on serum glucose concentrations in rats. Rats were intravenously injected with moxifloxacin and samples of their arterial blood were collected periodically. Serum glucose concentrations increased with moxifloxacin at 100 mg/kg, and temporal elevations were observed in serum epinephrine and histamine concentrations. On the other hand, intravenous injection of moxifloxacin at 75 mg/kg did not affect serum glucose, epinephrine, or histamine concentrations. Serum immunoreactive insulin concentrations remained unchanged by moxifloxacin both at 75 and 100 mg/kg. In conclusion, moxifloxacin can induce histamine release, leading to an increase in serum epinephrine concentrations and hyperglycemia.

Encephalopathy Induced by High Plasma and Cerebrospinal Fluid Ceftriaxone Concentrations in a Hemodialysis Patient.

Encephalopathy is a rare side effect of cephalosporin treatment. We herein present a case of encephalopathy induced by ceftriaxone, a third-generation cephalosporin, in a patient with renal failure. An 86-year-old woman on maintenance hemodialysis received ceftriaxone for Helicobacter cinaedi bacteremia. Her mental status deteriorated during antibiotic treatment, and an electroencephalogram revealed triphasic waves predominantly in the frontal area. Her consciousness improved after the discontinuation of the antibiotic due to the suspicion of ceftriaxone-induced encephalopathy. This is the first reported case of encephalopathy associated with high plasma and cerebrospinal fluid ceftriaxone concentrations, and provides significant evidence for a causal relationship between the administration of ceftriaxone and the onset of encephalopathy.

HLA haploidentical hematopoietic cell transplantation using clofarabine and busulfan for refractory pediatric hematological malignancy.

Haploidentical hematopoietic cell transplantation (HCT) conditioning with clofarabine and target area under the blood concentration-time curve (AUC)-based busulfan adjustment was performed in three patients with refractory pediatric leukemia. The target AUC for two patients who had already received multiple transplantations was 3600 and 4000 µmol min/L, and that for the patient with Down's syndrome was 3000 µmol min/L. Regimen-related toxicity was well tolerated in all cases. All three maintained cytological remission throughout the follow-up period (between 31 and 167 weeks). Thus, haploidentical HCT conditioning with clofarabine and target AUC-based busulfan adjustment may be a preferable option for children with recurrent or refractory pediatric leukemia.

Effect of levofloxacin on serum glucose concentration in rats.

To clarify the mechanism of fluoroquinolone-induced abnormalities in blood glucose, the effect of levofloxacin on serum glucose concentration was investigated in rats. Rats received an intravenous injection of levofloxacin and their arterial blood was sampled periodically. The serum glucose concentration decreased after an injection of 100 mg/kg of levofloxacin, while it increased at levofloxacin 300 mg/kg. The serum immunoreactive insulin concentration increased as the dose of levofloxacin increased. The serum epinephrine concentration was rapidly elevated by levofloxacin at 300 mg/kg. The serum histamine concentration increased after injections of levofloxacin, 200 and 300 mg/kg. Diphenhydramine (1 mg/kg) antagonized the hyperglycemia induced by 300 mg/kg of levofloxacin. In an in vitro study, the release of epinephrine from the adrenal medulla in the presence of levofloxacin was determined. Levofloxacin (300 microg/ml) did not affect epinephrine release from the adrenal medulla. Levofloxacin can induce hypoglycemia and hyperglycemia in rats. Levofloxacin can promote histamine release, leading to an increased serum epinephrine concentration and hyperglycemia.

Effect of isoniazid on the pharmacodynamics of cefazolin-induced seizures in rats.

Both isoniazid (INH) and cefazolin (CEZ) can have serious adverse effects on the central nervous system (CNS), causing seizures. In this study, we investigated the effect of INH on the pharmacodynamics of CEZ-induced seizures in rats. Male Wistar rats pretreated with INH (150 mg/kg i.p.) or saline received an intravenous infusion of CEZ at 3.2 g/h/rat until the onset of seizures, then samples of cerebrospinal fluid (CSF), blood (for serum), and brain were obtained immediately. The administration of INH was associated with a reduction in the total dose of CEZ required to produce seizures. The concentrations of CEZ in serum, brain, and CSF in INH-treated rats at the onset of seizures were significantly lower than those in control rats. In rats coadministered with pyridoxine (150 mg/kg s.c.), the concentration of CEZ in CSF at the onset of seizures was significantly higher than that in rats administered INH only. These results suggest that INH potentiates the sensitivity of the CNS to CEZ-induced seizures, and that the increased sensitivity is associated with the inhibition of vitamin B(6) metabolism by INH.

Effect of cimetidine on pentamidine induced hyperglycemia in rats.

The antiprotozoal agent pentamidine, used for the treatment of Pneumocystis jirovecii pneumonia (PCP), is known to cause abnormalities in blood glucose homeostasis, such as hypoglycemia and hyperglycemia. Pentamidine has been reported to be a substrate of organic cation transporter 1 (OCT1). We investigated the combination effects of cimetidine, an OCT1 inhibitor, on the pharmacokinetics of pentamidine and on pentamidine-induced hyperglycemia. Pentamidine was infused intravenously to rats for 20 min at a dose of 7.5 or 15 mg/kg and serum samples were obtained periodically. The serum concentration of glucose did not change significantly after pentamidine infusion at 7.5mg/kg, while it increased with pentamidine at 15 mg/kg, and the maximal concentration of glucose was 167 ± 36 mg/dl, 30 min after the start of pentamidine infusion. Cimetidine (50mg/kg) enhanced the pentamidine-induced elevation of glucose concentration and the maximal concentration of glucose was 208 ± 33 mg/dl in the pentamidine 15 mg/kg treated group. Cimetidine combination significantly reduced total body clearance of pentamidine and increased pentamidine concentrations in the liver, kidneys, and lungs. A significant correlation was found between changes in serum glucose concentrations and serum concentrations of pentamidine 30 min after the start of pentamidine infusion. These results suggest that the hyperglycemic effect of pentamidine is dependent on the concentration of pentamidine and can be enhanced by cimetidine combination.

Pharmacodynamics of cibenzoline-induced hypoglycemia in rats.

Hypoglycemia is one of the serious adverse effects induced by cibenzoline (CBZ), an antiarrhythmic agent. In order to clarify the pharmacodynamics of CBZ-induced hypoglycemia, CBZ was administered intravenously to conscious rats at a dose of 5, 10 or 20 mg/kg and serum samples were collected periodically to determine the concentrations of CBZ, insulin and glucose. The pharmacokinetics of CBZ showed nonlinear characteristics and could be described by a two-compartment model with Michaelis-Menten elimination kinetics. CBZ induced a rapid increase in the serum concentration of insulin. As the CBZ dose was increased, a greater hypoglycemic effect occurred. The indirect response model was applied to account for the CBZ-induced increase in insulin secretion and the subsequent decrease in serum glucose. A linear relationship was assumed between the serum concentration of CBZ and its stimulating effect on insulin secretion. A nonlinear relationship was assumed between the serum concentration of insulin and its stimulating effect on the elimination of serum glucose. The time courses of serum concentrations of CBZ, insulin and glucose after intravenous injection of CBZ could be described by the pharmacokinetic and pharmacodynamic model developed. This approach will be useful for the identification of variable factors related to CBZ-induced hypoglycemia.

Gatifloxacin-induced histamine release and hyperglycemia in rats.

Gatifloxacin, a fluoroquinolone antimicrobial agent, has been reported to cause both hypoglycemia and hyperglycemia in diabetic and non-diabetic patients. The purpose of the present study was to investigate the mechanism of gatifloxacin-induced hyperglycemia in normal and diabetic rats. Rats received a single intravenous injection of gatifloxacin and samples of their arterial blood were collected periodically. Diabetic rats were produced by the injection of streptozotocin and nicotinamide. In normal rats, the concentration of serum glucose decreased after the injection of gatifloxacin at 50mg/kg, while it increased with gatifloxacin at 100mg/kg. The concentrations of serum epinephrine and histamine increased after the injection of gatifloxacin at 100mg/kg. The increases in serum glucose and epinephrine concentrations were reduced by pretreatment with diphenhydramine at 1mg/kg. In diabetic rats, the concentration of serum glucose actually increased after the injection of gatifloxacin at 50mg/kg, concomitant with increases in the serum epinephrine and histamine concentrations. The concentration of serum immunoreactive insulin slightly increased after the injection of gatifloxacin at 50mg/kg. In addition, repeated oral administration of gatifloxacin to rats at 300 mg/kg twice a day for 7 days did not change glucose tolerance. In conclusion, gatifloxacin-induced release of histamine can contribute to an increase in the serum epinephrine concentration and hyperglycemia in normal rats. In diabetic rats, lower doses of gatifloxacin can induce hyperglycemia owing to the low level of insulin secretion that they exhibit compared with normal animals.

Concurrent administration of intravenous systemic and intravitreal methotrexate for intraocular lymphoma with central nervous system involvement.

Intraocular lymphoma (IOL) is rare lymphoma that frequently infiltrates the central nervous system (CNS). An optimal treatment has not been established, and its prognosis is quite poor. We treated three IOL patients with CNS involvement by concurrent administration of intravenous and intravitreal methotrexate (MTX) injection. The intraocular lesion responded in all patients. One patient achieved complete response (CR), whereas the other 2 patients were in partial response for CNS lesion, added whole brain radiation and achieved CR. In 3 eyes of 2 patients, an intravitreal MTX injection (vMTX) was administered 2 h after a systemic MTX injection (sMTX) and the intravitreal MTX concentration was measured twice: 2 h after sMTX and 24 h after vMTX. The half-life of MTX in the vitreous fluid was estimated to be 12.4-21.5 h by assuming the first-order elimination kinetics. Although the concentration was still high 24 h after vMTX (69.94-82.89 muM), there were no ocular complications. The serum MTX concentration was not influenced by adding vMTX to sMTX. Grade 3 adverse event, leukocytopenia, was observed in only 1 patient. No grade 4 event was observed. Although further evaluation is required, concurrent sMTX and vMTX may be effective for IOL with CNS involvement.